Effects Of GM1 Ganglioside Treatment Research Articles

The Behavioral and Immunological Effect of GM-1 Ganglioside on Nerve Root Regeneration Following C5 Nerve Root Avulsion in a Rat Model

Preganglionic nerve root avulsion precludes sensory return, but motor regeneration is possible with sparing of motoneurons. The effect of GM-1 ganglioside treatment was studied with parallel evaluation of the autoimmune response. Rats (N=64) received injections of either GM-1 ganglioside or saline for 30 days following either C5 root avulsion or a hemilaminectomy control. The Bertelli grooming test assessed functional return. Before sacrifice at 5 months, serum was collected for enzyme-linked immunoabsorbent assay testing. Only 44% of the rats treated with ganglioside had a good functional outcome compared with 50% for controls. Although 17% of the rats developed anti GM-1 antibodies, there was no functional or histological evidence of neuropathy in any of the rats. We conclude that ganglioside treatment did not enhance recovery from peripheral nerve injury. Although an immune response was present in some rats, no overt signs of neuropathy were observed.

Sciatic nerve axotomy in aged rats: response of motoneurons and the effect of GM1 ganglioside treatment

The number, size, and staining intensity of choline acetyltransferase (ChAT)-immunopositive cells in the retrodorsal lateral nucleus (RDLN) of the spinal cord were studied in young (3–5 months old) and aged (22–24 months old) rats following left sciatic nerve distal transection (axotomy) and treatment with GM1 ganglioside. The cell size and the ChAT immunostaining density were decreased in the RDLN of non-manipulated as well as in the contralateral intact side of axotomized aged rats. Axotomy had no effect on the number of RDLN motoneurons in both aged and young rats. In the young rats, there was a decrease in the size of motoneurons 7 days post-axotomy and a partial spontaneous recovery occurred by 21 days. Axotomy did not reduce further the size of aged motoneurons, however. The ChAT staining intensity of the axotomized RDLN declined in both age groups after 7 days, and there was spontaneous near normal recovery by 21 days. In the aged rats, GM1 administration for 7 days corrected the cell size and ChAT immunoreactivity of the contralateral intact RDLN. With regard to axotomized RDLN neurons, 7 days of GM1 restored the cell size but not the ChAT immunostaining in young animals. The same treatment schedule, however, corrected both cell size and staining in aged rats. Administration of GM1 for 21 days had no further effect on the morphometric parameters of the axotomized motoneurons in aged rats, but slightly enhanced the recovery of ChAT immunostaining in young rats. Thus, it appears that GM1 facilitates the phenotypic recovery of RDLN motoneurons during aging and after axotomy.

Functional and structural effects of GM-1 ganglioside treatment on peripheral nerve grafting in the rat.

Peripheral nerve regeneration after traumatic injury and standard repair with a nerve autograft is usually incomplete. This study tested the influence of graft vascularity and pharmacological intervention with GM-1 ganglioside on nerve regeneration in a rat sciatic nerve model. Controls included an unoperated contralateral side and sham-operated groups either with or without the GM-1. During the 5 months of recovery, locomotion was tested by the sciatic function index (SFI). At killing, anesthetized animals were prepared for nerve conduction velocity (NCV) studies, followed by the wet weight of the gastrocnemius muscle (expression of atrophy), toe-chewing (expression of lesion severity and sensory loss), and histological examination of the nerve segments. The SFI showed a slight but significant recovery for both the vascular and avascular groups (34% at 20 weeks), but when GM-1 ganglioside treatment was included, the SFI was poor throughout (20-33%). The average NCV of the graft groups without GM-1 was 46% to 57% of the normal nerve (52.7 m/s), whereas for the groups treated with GM-1, it was 63% to 64% of normal; treatment of the non-vascular graft group significantly improved recovery. A uniformly poor recovery from muscle atrophy was seen for all nerve graft groups (62-67%) compared with normal controls. The mean number of toes per foot chewed was 1.9 and 2.4 in graft groups without GM-1 treatment and 0.9 and 1.3 in graft groups treated with GM-1. This treatment significantly reduced both the extent and the number of animals exhibiting autotomy. The qualitative microscopic appearance of the distal nerve segment in all surgical groups was similar. We conclude that the systemic addition of GM-1 ganglioside enhances only some aspects of regeneration in grafted nerves, possibly with a preferential effect on sensory nerve regeneration and functional recovery.

Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [3H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [3H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism. Synapse 36:120–128, 2000. © 2000 Wiley-Liss, Inc.

Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys.

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [(3)H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [(3)H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism.

Effects of GM1 ganglioside treatment on dopamine innervation of the striatum of MPTP-treated mice.

GM1 ganglioside has been shown to stimulate repair of the nigrostriatal dopamine system after injury. This has been particularly evident in the mouse MPTP model of Parkinsonism. Systemic administration of GM1 has been shown to increase striatal dopamine levels and lead to increased density of substantia nigra pars compacta neurons after MPTP administration versus mice treated with MPTP and saline. The purpose of the present study was to assess regional changes in dopaminergic innervation of the striatum of mice treated with MPTP then GM1. Studies consisted of [3H] mazindol binding of dopamine uptake sites, postmortem striatal tissue dopamine levels, and peak dopamine release in response to KCl stimulation measured in vivo. Results showed that measures of dopamine innervation were significantly increased in most striatal areas in MPTP+GM1-treated mice compared to MPTP+saline-treated controls. The results indicate that GM1 treatment increases measures of dopaminergic innervation after an MPTP lesion, possibly through sprouting of new terminals or increased dopamine production and release from remaining terminals.

Behavioral effects of GM1 ganglioside treatment and intrahippocampal septal grafts in rats with fimbria-fornix lesions.

The monosialoganglioside GM1 is a compound with neurotrophic properties found to foster functional recovery in various paradigms of brain damage. The present experiment examined whether systemic treatment with GM1 may facilitate behavioral recovery in rats with fimbria-fornix lesions and intrahippocampal grafts rich in cholinergic neurons. Among 68 Long-Evans female rats, 46 sustained a bilateral electrolytic lesion of the fimbria and the dorsal fornix and 22 were sham-operated. Fourteen days later, half the lesioned rats were subjected to intrahippocampal grafts of a fetal septal cell suspension. Starting a few hours after lesion surgery and over a 2-month period, half the rats of each surgical treatment group received a daily injection of GM1 (30 mg/kg i.p.), the other half being injected with saline as a control. All rats were subsequently tested for locomotor activity and radial maze learning. The lesions induced locomotor hyperactivity and impaired learning performances in both an uninterrupted and an interrupted radial maze testing procedure. In all rats with surviving grafts, the grafts had provided the hippocampus with a new and dense organotypic acetylcholinesterase-positive innervation pattern which did not differ between saline- and GM1-treated subjects. The scores/performances of the rats that had received only the grafts or only the GM1 treatment did not differ significantly from those of their respective lesion-only counterparts. However, in the radial-arm maze task, the grafted rats given GM1 showed improved learning performances as compared with their saline-treated counterparts: they used more efficient visit patterns under the uninterrupted testing conditions and made fewer errors under the interrupted ones. The results suggest that GM1 treatment or intrahippocampal grafts used separately do not attenuate the lesion-induced behavioral deficits measured in this experiment. However, when GM1 treatment and grafts are used conjointly, both may interact in a manner allowing part of these deficits to be attenuated.

Differential effects of GM1 ganglioside treatment on glial fibrillary acidic protein content in the rat septum and hippocampus after partial interruption of their connections.

The glial fibrillary acidic protein (GFAP) content was investigated using immunoblotting techniques in the septum and hippocampus of the rat after bilateral lateral fimbria transection. Seven days after surgery GFAP content increased significantly both in the septum (140% of control) and hippocampus (120% in dorsal, the less denervated, and 145% in the most denervated ventral part), indicating the occurrence of reactive gliosis. The GM1 treatment caused statistically significant attenuation of GFAP increment in all hippocampal parts. In contrast, GM1 treatment has no influence on the increase of GFAP content in the septum. Results suggest a differential effect of GM1 on the two gliotic reactions formed as a consequence of the lesion at the level of the source of innervation (septum) and the target (hippocampus).

GM1 ganglioside treatment reduces visual deficits after graded crush of the rat optic nerve

Despite numerous reports of beneficial effects of GM1 ganglioside treatment following brain lesions in animals, the underlying neurobiological mechanism of ganglioside-induced functional restoration is still unclear. In order to obtain a better insight into this question, we have made use of a newly developed animal model of brain injury that would potentially permit us to determine the causal relationships(s) among behavioral and neuroanatomical/neurochemical parameters of restoration of function. Following graded crush of the adult rat optic nerve, we have treated the rats with intraperitoncally injected gangliosides and studied the functional outcome with electrophysiological and behavioral parameters. The electrophysiological recprding of the compound action potential (CAP) from excised rat optic nerve revealed a significant loss of CAP throughout the first 2 weeks after the injury. However, when rats were treated daily for 7 days with GM1-gangliosides, the CAP measured 10 days after the crush was significantly larger compared to operated controls without treatment. Thus, GM1 appeared to be capable of delaying or partially preventing retinal ganglion cells or their axons from secondary degeneration. Loss of visual function was also evident on the behavioral level of analysis: when rats with unilateral optic nerve crush were evaluated in a visual orienting paradigm, the rats revealed deficits in their ability to orient towards small, moving visual stimuli. However, within about 2 weeks, the animals recovered spontaneously to near normal performance. Daily treatment with GM1-gangliosides was found to significantly improve outcome, largely due to a reduction of the immediate post-lesion deficit. In a second behavioral experiment we also created graded crush in rats bilaterally and evaluated the animals visual capacities in a two-choice brightness discrimination task. In this park, an initial loss of function was followed by recovery within about 2 weeks, but GM1 treatment was without beneficial effects in this paradigm. It is concluded that GM1 improves outcome after graded crush of the adult rat optic nerve, although it appears that improved function needs to be documented with sufficiently sensitive behavioral assays.

Effect of GM1 ganglioside treatment on the recovery of dopaminergic nigro-striatal neurons after different types of lesion.

The effect of GM1 ganglioside treatment on the recovery of biochemical and behavioral parameters which define the activity of nigro-striatal dopaminergic systems has been investigated in rats after different types of lesion. GM1 favours the recovery of tyrosine-hydroxylase activity, of the number and affinity of 3H-N-n-propyl-norapomorphine binding sites in the striatum of the lesioned side and reduces the apomorphine-induced rotational behavior after mechanical (i.e. unilateral hemitransection) but not after chemical (i.e. 6-OHDA injected in the substantia nigra) lesion. The source of regrowing dopaminergic nerve terminals in the striatum after hemitransection is mainly a response of intact remaining axons of the ipsilateral side. Moreover the contralateral nigro-striatal systems seems to play, through intrathalamic connections, an important role in regulating the GM1-induced increase of the tyrosine-hydroxylase activity.

Effect of GM1 ganglioside treatment on postlesion responses of cholinergic enzymes in rat hippocampus after various partial deafferentations.

The effect of intramuscular administration of monosialoganglioside (GM1) on postlesion responses of choline acetyltransferase and acetylcholinesterase activity in partially deafferented rat hippocampus was studied at various survival times. Lesions partially destroying the medioventral, septal area, or lesions performed in supracallosal stria including corpus callosum and cingulum evoked cholinergic denervation of the hippocampus, while those made in entorhinal cortex resulted in partial glutamatergic deafferentation. GM1 treatment potentiates the responses of both cholinergic enzymes, independently of whether the partial deafferentation was homo- or heterotypical. These data indicate that GM1 may facilitate the regrowth of new cholinergic nerve terminals. However, an effect on other compensatory processes, especially in the first postoperative period, is also possible.